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104 Editorial

Fluoride 46(3)104–117 July-September 2013

Fluoride- and electromagnetic radiation-induced genotoxicity and impaired melatonin secretion Spittle

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FLUORIDE- AND ELECTROMAGNETIC RADIATION-INDUCED GENOTOXICITY AND IMPAIRED MELATONIN SECRETION SUMMARY: Rao and Thakur have shown that the antioxidants melatonin and alma (Emblica officinales, Indian gooseberry) are effective, both individually and in combination, against fluoride-induced genotoxicity in human peripheral blood lymphocyte cells, which was first described in humans in 1994. Some animal and human work also suggests that fluoride (F) can impair the defensive response to genotoxicity by being deposited in high concentrations in the pineal gland and, through an enzyme-inhibiting action, reducing the secretion of melatonin, a powerful antioxidant able to eliminate free radicals and protect DNA. In having the capacity to be both genotoxic and impair melatonin secretion, F is similar to electromagnetic radiation, at power line frequencies and above, and both have very low or zero thresholds for causing toxicity. In view of the seriousness of neoplasia, the effect of fluoride on melatonin secretion warrants further research. Keywords: Alma; Electromagnetic radiation and genotoxicity; Electromagnetic radiation and melatonin; Fluoride and genotoxicity; Fluoride and melatonin; Melatonin; Pineal inhibition by electromagnetic radiation; Pineal inhibition by fluoride.

In this issue Rao and Thakur (pp. 128-34) show that the antioxidants melatonin (N-acetyl-5-methoxytryptamine) and alma (Emblica officinales, Indian gooseberry) are effective, both individually and in combination, against fluorideinduced genotoxicity in human peripheral blood lymphocyte cells. The study follows several previous studies1-3 since 2006 on the ameliorative effects of melatonin on fluoride-induced toxicity from Professor Mandava V Rao’s group at Gujarat University, Ahmedabad, where the genotoxic effects for fluoride (F) in drinking water were first described in 1994 by Sheth, Multani, and Chinoy.4 Professor Niloufer Chinoy’s team found increased sister chromatid exchanges (SCEs) in persons exposed to F in the endemic areas of North Gujaret (F– 1.95–2.2 mg/L or ppm) compared to those living in Ahmedabad (F– 0.6–1.0 mg/L). Rao and Thakur note that exposure to radioactive and genotoxic agents may affect the cell cycle and increase the frequency of SCEs, average generation time, and population doubling time. They found that F can bind to Ran protein, which is involved in the arrangement of microtubules and regulates nuclear cytoplasmic transport during the three phases of the interphase part of the cell cycle: G1 (cells increase their size), S (DNA replication occurs), and G2 (significant protein synthesis occurs, mainly for the production of microtubules).5-6 SCEs occur during DNA replication as cells pass to S phase, and F affects the cell cycle, cell membrane, and protein leading to an increase in SCE frequency and a decreased cell cycle proliferative index. Several studies have linked F exposure to neoplasia including a 2006 report by Bassin, Wypij, Davis, and Mittleman, which found, in males, an association between F exposure in drinking water during childhood and the incidence of osteosarcoma before the age of 20.7-12 Rao and Thakur record that melatonin, secreted from the pineal gland, along with its by-products, is an extremely powerful antioxidant that is able to eliminate free radicals, such as reactive oxygen species, and has a particular role in

105 Editorial

Fluoride 46(3)104–117 July-September 2013

Fluoride- and electromagnetic radiation-induced genotoxicity and impaired melatonin secretion Spittle

105

protecting DNA. Reduced melatonin secretion has been linked to DNA strand breaks, chromosome aberrations, and impaired immune system competence.13,14 Thus genotoxicity may result from the direct action of a toxic agent or indirectly through the toxic agent reducing the secretion of the free radical scavenger melatonin. In addition to the references above indicating a direct toxic action by F,1-4,6 there is a literature reporting that F may reduce melatonin secretion. Luke found that prepubescent Mongolian gerbils (Meriones unguiculatus) fed a high-F diet had significantly lower pineal melatonin production than those fed a low-F diet, and sexual maturity occurred earlier in the females.15,16 Melatonin activates cAMP-sensitive gene expression in the pars tuberalis of the anterior pituitary gland by the sensitization of adenylyl cyclase, thus synchronizing the suprachiasmatic nucleus of the hypothalamus and clock-controlled genes in the peripheral tissue which control the onset of puberty.17,18 She noted that the possibility of a species difference between humans and gerbils did not allow the extrapolation of the gerbil data to humans but expressed some concern about the possible implications of the results of the animal studies. She observed that F was now being introduced to children to protect against dental caries at a much earlier stage of human development than had ever occurred before. If the resulting increased plasma-F levels have caused a decline in the levels of circulating melatonin during early human development, significant physiological consequences may have already occurred. Luke found that the range for the pineal F content in eleven human cadaver pineal glands, from persons aged 72–100 yr, was 14–875 mg/kg with a mean of 296±257 mg/kg (wet weight), higher than that in corresponding muscle, 0.5±0.4 mg/kg (wet weight), and that it was directly correlated to the pineal calcium content: r=0.73, p